Disordered Binding of Small Molecules to Aβ(12–28)

Disordered binding of small molecules to Aβ12-28 DISORDERED BINDING OF SMALL MOLECULES TO Aβ12-28

Background: Inhibition of pathogenic protein aggregation by small molecules is poorly understood. Results: Aggregation inhibitors alter the free energy landscape of a relevant fragment of Alzheimer's amyloid-β protein in subtle but complex fashion. Conclusion: Intrinsic disorder of disease proteins persists at the level of binding small molecules. Significance: Hallmark characteristics and effi...

Disordered binding of small molecules to Aβ(12-28).

In recent years, an increasing number of small molecules and short peptides have been identified that interfere with aggregation and/or oligomerization of the Alzheimer β-amyloid peptide (Aβ). Many of them possess aromatic moieties, suggesting a dominant role for those in interacting with Aβ along various stages of the aggregation process. In this study, we attempt to elucidate whether interact...

Mechanisms of small-molecule binding to intrinsically disordered proteins.

IDPs (intrinsically disordered proteins) play crucial roles in many important cellular processes such as signalling or transcription and are attractive therapeutic targets for several diseases. The considerable structural flexibility of IDPs poses a challenge for rational drug discovery approaches. Consequently, structure-based drug design efforts to date have mostly focused on inhibiting inter...

INTERACTION OF PROTEINS WITH SMALL MOLECULES

Discovery of Small Molecules that Inhibit the Disordered Protein, p27Kip1

Disordered proteins are highly prevalent in biological systems, they control myriad signaling and regulatory processes, and their levels and/or cellular localization are often altered in human disease. In contrast to folded proteins, disordered proteins, due to conformational heterogeneity and dynamics, are not considered viable drug targets. We challenged this paradigm by identifying through N...